Neuropsychiatric AEs resolve after switch to doravirine-based ARV regimens

Switching to a doravirine-based antiretroviral (ARV) regimen resolves neuropsychiatric adverse events (NPAEs) that were ongoing during a prior efavirenz-based regimen in DRIVE-AHEAD, with few NPAEs persisting 96 weeks after switching — a finding also seen in DRIVE-FORWARD, as shown in post hoc analyses of the open-label extensions (OLEs) of the two phase III trials.

In DRIVE-AHEAD, 9.7 percent of patients originally randomized to receive efavirenz/emtricitabine/tenofovir disoproxil fumarate (efavirenz/FTC/TDF) reported ongoing NPAEs at the completion of the 96-week double-blind (DB) phase. After switching to coformulated doravirine/lamivudine/TDF (doravirine/3TC/TDF) upon entering the OLE, 73.1 percent of these patients had NPAEs resolved or were resolving by week 192.

NPAEs were prespecified to encompass sleep disorders, depression and related disorders, dizziness, altered sensorium, and psychotic disorders.

In DRIVE-FORWARD, 6.4 percent of patients originally randomized to receive ritonavir-boosted darunavir (darunavir/r) plus two nucleos(t)ide reverse transcriptase inhibitors (NRTIs) during the DB phase had ongoing NPAEs at week 96. Following a switch to OL doravirine plus two NRTIs, 40 percent of these patients reported resolution of NPAEs by week 192. [J Acquir Immune Defic Syndr 2025;99:81-86]

After switching to the study-specific doravirine-based regimen in the OLEs of DRIVE-AHEAD and DRIVE-FORWARD, NPAEs persisted to week 192 in 2.6 percent and 3.9 percent of participants, respectively.

“Overall, in both trial OLEs, NPAEs persisted in approximately 3–4 percent of participants 96 weeks after switching to a doravirine-based regimen, possibly representing the background rate for these events,” said lead author Dr Graeme Moyle, an HIV specialist at Chelsea and Westminster Hospital, London, UK. “This suggests a doravirine-based regimen may be a good option for adults with HIV and baseline NP symptoms or for those experiencing NPAEs with other ARV regimens.”

CNS safety

DRIVE-AHEAD (n=734) and DRIVE-FORWARD (n=769) were pivotal, multicentre, randomized, active-controlled noninferiority trials in ARV-naïve adults with HIV-1 infection.

DRIVE-AHEAD compared single-tablet doravirine/3TC/TDF vs coformulated efavirenz/FTC/TDF for virologic suppression at 48 weeks, while DRIVE-FORWARD compared doravirine plus two NRTIs vs darunavir/r plus two NRTIs for the same primary efficacy endpoint. [Clin Infect Dis 2019;68:535-544; Lancet HIV 2018;5:e211-e220]

The current analyses focused on participants who were initially randomized to the comparator regimen arm, completed 96-week DB treatment, and transitioned to the respective noncontrolled OLE. In DRIVE-AHEAD, 269 participants did so and switched to doravirine/3TC/TDF, and in DRIVE-FORWARD, 233 did so and switched to doravirine plus two NRTIs.

Despite both being non-NRTIs, doravirine has been established as having superior central nervous system (CNS) safety vs efavirenz. [Antivir Ther 2019;24:425-435]

For example, in the 96-week results of DRIVE-AHEAD, the incidence of NPAEs was significantly lower with doravirine/3TC/TDF vs efavirenz/FTC/TDF (26.4 percent vs 58.5 percent; difference, −32.1 percentage points; p<0.001). [Clin Infect Dis 2021;73:33-42]

This superiority may reflect the lesser propensity for off-target activities of doravirine vs efavirenz, considering that both attain adequate CNS penetration in virologically suppressed patients. [ACS Infect Dis 2020;6:64-73]

“ARVs should not precipitate or exacerbate NP symptoms,” stated Moyle. “According to current guidelines, persistent or debilitating NPAEs should prompt substitution of efavirenz with doravirine, etravirine, or a boosted protease inhibitor.”

The current investigation accordingly quantified the resolution of NPAEs in those switching to doravirine.

New-onset NPAEs

Moyle and colleagues also examined new-onset NPAEs occurring after switching between weeks 96 and 192.

During this 22-month period in the OLEs, 9.3 percent of participants who switched to doravirine/3TC/TDF in DRIVE-AHEAD and 7.7 percent of those who switched to doravirine plus two NRTIs in DRIVE-FORWARD experienced new-onset NPAEs. By week 192, 60 percent and 61.1 percent of new-onset NPAEs on the respective doravirine-based regimens had resolved or were resolving.